The specific aim of this investigation is to clarify the biochemical events and consequences involved in the redirection of phospholipid metabolism by some cationic amphiphilic drugs (CADs) in clinical use. Several drugs with the physicochemical properties of CADs have been shown when used chronically to cause phospholipidosis as side effect, consisting of multilamellar cytoplasmic inclusion bodies with the characteristics of secondary lysosomes. We shall concentrate especially on drugs which are efficacious in mental and nervous disorders and assess primarily their effects on phospholipids in cerebral cortex, cerebellum, limbic structures and neuroblastoma cells. To elucidate the cellular mechanisms by which CADs cause alterations in nervous tissue phospholipid metabolism, we shall examine the effects of chlorpromazine, desipramine and propranolol on lipid levels and the enzymes involved in the metabolism of phosphatidic acid, diacylglycerol, phosphatidylcholine and polyphosphoinositides. In view of the postulated relationship between CADs and Ca2+, we also propose to study their effects on Ca2+ fluxes and levels and on phospholipid biosynthesis when the charges on membranes are modified through changes in pH or treatment with phospholipases or neuraminidase. In order to define further the determining factors for the action of CADs we aim to establish the distribution of the drugs in several organs, the characteristics of phospholipid metabolism in vitro after drug injection, and the influence of CADs on phospholipid labeling in vivo. The studies will be help in gaining a better understanding of the mechanism of phospholipidosis induction, in predicting the lipidosis-inducing ability of drugs, in identifying the tissue most likely to be affected and in preventing or minimizing the appearance of drug-induced lipidosis. They will also be useful in clarifying certain features of normal cellular metabolism and of the role of calcium.